Recently, great efforts have been devoted to synthesizing magnetic nanoparticles, which are able to induce the production of heat when an oscillating magnetic field is applied to them (Duguet et al., Nanomed., 2006, 1, 157-168) and that can be easily manipulated using magnetic fields. These features have led to the idea that magnetic nanoparticles may be helpful in the destruction or elimination of tumors through hyperthermia or thermoablation or that they can be used to release drugs at specific localized regions of the body. This field of research is often designated as alternating magnetic field (AMF) hyperthermia since it requires the application of an alternating magnetic field to induce the production of heat by the nanoparticles. In previous work, the heat has been induced using chemically synthesized nanoparticles, mainly in the form superparamagnetic iron oxide nanoparticles (SPION), which were either mixed in solution or mixed with cells or administered to a living organism. The anti-tumoral activity of these heated nanoparticles has also been evaluated both on animal models and clinically on humans. An overview of the work carried out previously is presented in the references listed hereafter (Bae et al., J. Controlled Release, 2007, 122, 16-23; Ciofani et al., Med. Hypotheses, 2009, 73, 80-82; De Nardo, Clin. Cancer Res., 2005, 11, 7087s-7092s; De Nardo et al., J. Nucl. Med., 2007, 48, 437-444; Higler et al., Radiology, 2001, 218, 570-575; Ito et al., Cancer. Sci., 2003, 94, 308-313; Ito et al., J. Biosci. Bioeng., 2003, 96, 364-369; Ito et al, Cancer Lett., 2004, 212, 167-175; Ito et al., Cancer Immunol. Immun., 2006, 55, 320-328; Johannsen et al., Int. J. Hyperthermia, 2005, 21, 637-647; Johannsen et al., Int. J. Hyperthermia, 2007, 52, 1653-1662; Jordan et al., Int. J. Hyperthermia, 1993, 9, 51-68; Kawai et al., Prostate, 2005, 64, 373-381; Kawai et al., Prostate, 2008, 68, 784-792; Kikumori et al., Breast Cancer Res. Treat., 2009, 113, 435-441, Maier-Hauff et al., J. Neurooncol., 2007, 81, 53-60; Oberdörster et al., Environ. Health Persp., 2005, 113, 823-839; Ponce et al., Int. J. Hyperthermia, 2006, 22, 205-213; Tai et al., Nanotechnology, 2009, 20, 135101; Thisen et al., Int. J. Hyperthermia, 2008, 24, 467-474).
At this time, there are at least three companies that develop cancer therapy using the heat generated by magnetic nanoparticles when the latter are exposed to an alternating magnetic field. These companies are Sirtex (an Australian company), Magforce (a German company) and Aspen Medisys (an American company previously Aduro Biotech and Triton Biosystem). The patterns that have been published by these companies describe various ways of using the heat generated by chemically synthesized magnetic nanoparticles for cancer therapy (Sirtex: US2006167313 or WO 2004/064921; Triton Biosystems now Aspen Medisys, LLC: US2003/0028071; Magforce: US2008/0268061).
Although significant progress has been made in the area of nanoparticle cancer therapy, concerns have been raised regarding the toxicity induced by the presence of the chemically synthesized nanoparticles in the body (Habib et al., J. Appl. Phys., 2008, 103, 07A307-1-07A307-3). In order to minimize the potential side effects arising during the clinical treatments, the quantity of nanoparticles administered needs to be as small as possible while still retaining their desired effect. For that, magnetic nanoparticles have to generate a sufficiently large amount of heat, i. e. significant specific absorption rates (SAR).
Therefore, there is a need for magnetic nanoparticles having a higher heating capacity than that usually obtained with chemically synthesized nanoparticles. This will be useful to reduce the amount of magnetic material needed to heat a biological tissue or cell. This can be achieved by using nanoparticles with either large volumes or with high magnetocrystalline anisotropy (Hergt et al., J. Phys. Condens. Matter, 2006, 18, S2919-S2934).
There is also a need to develop magnetic nanoparticles that can have such good properties and the ability to target a tissue or a cell.
In part due to their large volume, the magnetosomes synthesized by magnetotactic bacteria produce a larger amount of heat than the chemically synthesized nanoparticles when they are subjected to an oscillating magnetic field. This has been shown for bacterial magnetosomes mixed in solution (Hergt et al., J. Phys. Condens. Matter, 2006, 18, S2919-S2934; Hergt et al., J. Magn. Magn. Mater., 2005, 293, 80-86; Timko et al., J. Mag. Mag. Mat., 2009, 321, 1521-1524). In the above references, the type of bacterial magnetosomes used to carry out the experiments has not been clearly identified.
The magnetosomes are intracellular, membrane-bounded, nanometer-sized single-magnetic-domain crystals of the iron oxide magnetite (Fe3O4) or iron sulfide greigite (FeS4) that are synthesized by magnetotactic bacteria. The magnetosomes composed of magnetite can become oxidized to maghemite after extraction from the bacteria. The magnetosomes are usually arranged as a chain within the bacteria, but individual magnetosomes can also be found. The bacteria appear to use the magnetosomes to navigate in the Earth's geomagnetic field and help them to locate and maintain optimal conditions for their growth and survival (Bazylinski et al., Nat. Rev. Microbiol., 2004, 2, 217-230). Magnetosomes and magnetosome magnetite crystals have been shown to be useful in a number of scientific, commercial and health applications. For example, they can be used to detect single nucleotide polymorphism, to extract DNA or to detect magnetically bio-molecular interactions. They can also be used in immunoassay and receptor-binding assay or in cell separation (Arakaki et al., J. R. Soc. Interface, 2005, 5, 977-999). It has been suggested that bacterial magnetosomes could be inserted within liposomes for drug delivery purposes (U.S. Pat. No. 6,251,365B1). However, very few experimental proofs have been given in this pattern and the heating capability of such liposome has not been demonstrated or suggested. The anti-cancerous activity of a complex formed by bacterial magnetosomes and doxorubicin has been shown experimentally (Sun et al., Cancer Lett, 2007, 258, 109-117). In this case, the anti-cancerous activity is due to the presence of doxorubicin and not to a treatment induced by heat. In the end, bacterial magnetosomes have not been proven to be useful for in vitro or in vivo heat treatment of tumor or cancer cells.
Finally, two recent studies briefly address the issue raised by the potential toxicity of bacterial magnetosomes in rats and don't report any sign of toxicity (Sun et al., J. Nanosci. Nanotechnol., 2009, 9, 1881-1885; Sun et al, Sun et al, Nanotoxicology, 2010, 4, 271-283).